Process for preparing a crystalline form of halobetasol propionate

ABSTRACT

The present invention provides a process for preparing a crystalline form of halobetasol propionate, comprising the step of crystallizing halobetasol propionate from absolute ethanol or a mixture of ethanol and water, wherein the crystalline form of halobetasol propionate is characterized by an x-ray powder diffraction pattern having peaks at 10.0, 11.6, 12.9, 13.4, 14.5, 16.4, 17.6, and 23.5±0.2 degrees 2θ.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.12/632,365, now U.S. Pat. No. 8,361,997, which is a divisional of U.S.application Ser. No. 11/399,732, filed Apr. 6, 2006, which claims thebenefit under 35 U.S.C. §119(e) of U.S. Provisional Application No.60/699,045 filed Apr. 7, 2005, the disclosures of which are incorporatedby reference in their entirety.

BACKGROUND OF THE INVENTION

1. Technical Field

This invention relates to a process for preparing a crystalline form ofhalobetasol propionate. The crystalline form of halobetasol propionateis characterized by an x-ray powder diffraction pattern having peaks at10.0, 11.6, 12.9, 13.4, 14.5, 16.4, 17.6, and 23.5±0.2 degrees 2θ.

2. Background Art

Halobetasol propionate((6α,11β,16β)-21-chloro-6,9-difluoro-11-hydroxy-16-methyl-17-(1-oxopropoxy)pregna-1,4-diene-3,20-dione;CAS #66852-54-8) is a high potency corticosteroid indicated for therelief of the inflammatory and pruritic manifestations ofcorticosteroid-responsive dermatoses. Halobetasol propionate has thefollowing chemical structure:

U.S. Pat. No. 4,619,921 (the '921 patent), issued in 1986, discloses thesynthesis of halobetasol propionate. The '921 patent further disclosesrecrystallization of halobetasol propionate using a solvent systemcontaining a mixture of methylene chloride and ether. The '921 patentdiscloses the melting point of the obtained crystalline form ofhalobetasol propionate (i.e., 220-221° C.), but does not expresslydisclose the x-ray diffraction pattern.

Since 1992, halobetasol propionate has been marketed and on sale underthe tradename ULTRAVATE® (Bristol-Myers Squibb Co., Princeton, N.J.) asan ointment and a cream. Both ULTRAVATE® ointment and ULTRAVATE® creamcontain 0.05% (w/w) halobetasol propionate as the active ingredient.Halobetasol propionate is soluble in organic solvents, but is insolublein water. Thus, halobetasol propionate is completely dissolved inorganic solvent-based ULTRAVATE® ointment, but remains as a suspendedsolid in water-based ULTRAVATE® cream. The literature contains nopublished characterization data regarding the specific crystalline formof halobetasol propionate used or contained in ULTRAVATE® ointment andcream.

U.S. Patent Application Nos. 2004/0138191 (the '191 application) and2004/0138192 (the '192 application) disclose x-ray powder diffraction,infrared, and differential scanning calorimetry characterization datafor a total of six (6) crystalline forms of halobetasol propionate(i.e., Forms I, II, III, IV, V and VI). According to the '191 and '192applications, crystallization using methylene chloride/ether (thesolvent system disclosed in the '921 patent) at a ratio of 5:1 resultsin crystalline Form I of halobetasol propionate.

The six (6) crystalline forms of halobetasol propionate disclosed in the'191 and '192 applications were prepared using eight (8) differentsolvent systems. Apparently, there is no predictable correlation betweenthe nature of the solvent system used (e.g., polarity, functionalgroups, hydrogen bonding ability) and the crystalline form ofhalobetasol propionate obtained. For example, crystallization fromisopropanol, methanol/water, and methanol (all alcoholic solventsystems) yields three (3) different crystalline forms of halobetasolpropionate (i.e., Forms III, IV, and VI, respectively). In addition,while crystallization from methylene chloride provides Form III ofhalobetasol propionate, crystallization from methylene chloride/etherprovides Form I of halobetasol propionate.

A disadvantage of the crystallization processes disclosed in the '191and '192 applications is that five (5) of the eight (8) solvent systemscontain methylene chloride, toluene, or methanol. Therefore, these five(5) solvent systems are toxic. In addition, only three (3) of the eight(8) solvent systems disclosed in the '191 and '192 applications provideForm III of halobetasol propionate. Preliminary studies from ourlaboratory indicate that Form III of halobetasol propionate matches thecrystalline form of halobetasol propionate present in ULTRAVATE® cream.

There is a continuing need for a process for preparing a crystallineform of halobetasol propionate, such as the crystalline form present inthe commercial ULTRAVATE® cream. There is a need for a process thatprovides a crystalline form of halobetasol propionate in high yield andsubstantially free of impurities, employs a non-toxic solvent system,and is suitable for commercial scale use.

SUMMARY OF THE INVENTION

The present invention provides a process for preparing a crystallineform of halobetasol propionate, comprising the step of crystallizinghalobetasol propionate from absolute ethanol or a mixture of ethanol andwater, wherein the crystalline form of halobetasol propionate ischaracterized by an x-ray powder diffraction pattern having peaks at10.0, 11.6, 12.9, 13.4, 14.5, 16.4, 17.6, and 23.5±0.2 degrees 2θ.

The crystalline form of halobetasol propionate is further characterizedby an infrared spectrum having absorption peaks at 1741, 1709, 1665,1627, and 1611±4 cm⁻¹. The crystalline form of halobetasol propionate isfurther characterized by a melting point of about 220° C. to about 221°C.

Preferably, the crystallization step is performed using absoluteethanol.

Preferably, the crystallizing step is performed using a mixture ofethanol and water at a vol/vol ratio between about 50:50 to about 100:0.Preferably, the crystallizing step is performed using a mixture ofethanol and water at a vol/vol ratio between about 50:50 to about 67:33.Preferably, the crystallizing step is performed using a mixture ofethanol and water at a vol/vol ratio of about 50:50.

Preferably, the crystallizing step is performed by a process comprisingthe steps of:

-   -   (a) preparing a solution of halobetasol propionate in absolute        ethanol or a mixture of ethanol and water; and    -   (b) inducing precipitation of a crystalline form of halobetasol        propionate.

Preferably, step (a) is performed by heating absolute ethanol or amixture of halobetasol propionate, ethanol, and water to an elevatedtemperature. More preferably, step (a) is performed by heating a mixtureof halobetasol propionate, ethanol, and water to a temperature of about60° C. to about 80° C.

Preferably, step (b) is performed by cooling the prepared solution. Morepreferably, step (b) is performed by cooling the prepared solution to atemperature of about 0° C. to about 25° C.

Preferably, step (b) is performed by adding water to the preparedsolution. More preferably, step (b) is performed by adding water to theprepared solution over the course of about 30 minutes to about 90minutes.

Preferably, the process for preparing a crystalline form of halobetasolpropionate further comprises the step of isolating the crystallizedhalobetasol propionate from the mixture of ethanol and water.Preferably, the isolating step is performed by filtration.

Preferably, the crystallizing step is repeated at least once.

Preferably, the crystalline form of halobetasol propionate is preparedas a single batch of at least about 100 grams. More preferably, thecrystalline form of halobetasol propionate is prepared as a single batchof at least about 500 grams. More preferably, the crystalline form ofhalobetasol propionate is prepared as a single batch of at least aboutone (1) kilogram.

The present invention further provides a process for preparing acrystalline form of halobetasol propionate, comprising the steps of:

-   -   (a) crystallizing halobetasol propionate from a first ethanol;    -   (b) isolating the crystallized halobetasol propionate from the        first ethanol;    -   (c) crystallizing the isolated halobetasol propionate from a        second ethanol; and    -   (d) isolating the crystallized halobetasol propionate from the        second ethanol,

wherein the crystalline form of halobetasol propionate is characterizedby an x-ray powder diffraction pattern having peaks at 10.0, 11.6, 12.9,13.4, 14.5, 16.4, 17.6, and 23.5±0.2 degrees 2θ.

The present invention further provides a process for preparing acrystalline form of halobetasol propionate, comprising the steps of:

-   -   (a) crystallizing halobetasol propionate from a first mixture of        ethanol and water;    -   (b) isolating the crystallized halobetasol propionate from the        first mixture of ethanol and water;    -   (c) crystallizing the isolated halobetasol propionate from a        second mixture of ethanol and water; and    -   (d) isolating the crystallized halobetasol propionate from the        second mixture of ethanol and water,

wherein the crystalline form of halobetasol propionate is characterizedby an x-ray powder diffraction pattern having peaks at 10.0, 11.6, 12.9,13.4, 14.5, 16.4, 17.6, and 23.5±0.2 degrees 2θ.

Preferably, the first mixture contains ethanol and water at a vol/volratio of about 67:33. Preferably, the second mixture contains ethanoland water at a vol/vol ratio of about 50:50.

Preferably, the crystalline form of halobetasol propionate has a purityof at least about 99.0% (w/w). More preferably, the crystalline form ofhalobetasol propionate has a purity of at least about 99.8% (w/w).

Preferably, the crystalline form of halobetasol propionate containsabout 0.1% (w/w) or less of each individual impurity. Examples ofimpurities include, but are not limited to, diflorasone, diflorasone17-propionate, halobetasol, diflorasone 21-propionate, diflorasone17-propionate 21-mesylate, and6α,9α-difluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17(R)-spiro-2′-[4′-chloro-5′-ethylfuran-3-(2′H)-one].

Preferably, the crystalline form of halobetasol propionate containsabout 0.02% (w/w) or less of diflorasone. Preferably, the crystallineform of halobetasol propionate contains about 0.02% (w/w) or less ofhalobetasol. Preferably, the crystalline form of halobetasol propionatecontains about 0.03% (w/w) or less of diflorasone 21-propionate.Preferably, the crystalline form of halobetasol propionate containsabout 0.03% (w/w) or less of diflorasone 17-propionate 21-mesylate.Preferably, the crystalline form of halobetasol propionate containsabout 0.05% (w/w) or less of6α,9α-difluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17(R)-spiro-2′-[4′-chloro-5′-ethylfuran-3-(2′H)-one].

The present invention further provides a commercial scale composition ofa crystalline form of halobetasol propionate prepared by the process ofthe present invention.

The present invention further provides a commercial scale composition ofa crystalline form of halobetasol propionate characterized by an x-raypowder diffraction pattern having peaks at 10.0, 11.6, 12.9, 13.4, 14.5,16.4, 17.6, and 23.5±0.2 degrees 2θ, wherein the composition containsabout 0.1% or less of each of diflorasone, diflorasone 17-propionate,halobetasol, diflorasone 21-propionate, diflorasone 17-propionate21-mesylate, and6α,9α-difluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17(R)-spiro-2′-[4′-chloro-5′-ethylfuran-3-(2′H)-one].

Preferably, the commercial scale composition contains about 0.1% (w/w)or less of each impurity present in the composition. Preferably, thecommercial scale composition contains about 0.05% (w/w) or less of eachof diflorasone, halobetasol, diflorasone 21-propionate, diflorasone17-propionate 21-mesylate, and6α,9α-difluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17(R)-spiro-2′-[4′-chloro-5′-ethylfuran-3-(2′H)-one].Preferably, the commercial scale composition contains about 0.03% (w/w)or less of each of diflorasone, halobetasol, diflorasone 21-propionate,and diflorasone 17-propionate 21-mesylate. Preferably, the commercialscale composition contains about 0.02% (w/w) or less of each ofdiflorasone and halobetasol.

Preferably, the commercial scale composition has a purity of at leastabout 99.5% (w/w). More preferably, the commercial scale composition hasa purity of at least about 99.7% (w/w). More preferably, the commercialscale composition has a purity of at least about 99.8% (w/w).

Preferably, the commercial scale composition is produced as a singlebatch of at least about 500 grams. More preferably, the commercial scalecomposition is produced as a single batch of at least about onekilogram.

BRIEF DESCRIPTION OF THE DIAGRAMS

FIG. 1 depicts an x-ray powder diffraction (XRPD) pattern of the presentcrystalline form of halobetasol propionate.

FIG. 2 depicts an infrared (IR) spectrum of the crystalline form ofhalobetasol propionate at commercial scale, obtained afterrecrystallizing from a mixture of ethanol and water (v/v ration of about67:33) and drying in vacuum oven.

FIG. 3 depicts an infrared (IR) spectrum of the crystalline form ofhalobetasol propionate at laboratory scale, obtained afterrecrystallizing from absolute ethanol and drying in vacuum oven.

FIG. 4 depicts an infrared (IR) spectrum of the crystalline form ofhalobetasol propionate at laboratory scale, obtained afterrecrystallizing from absolute ethanol and drying overnight on open airfor 24 hours.

FIG. 5 depicts an infrared (IR) spectrum of the crystalline form ofhalobetasol propionate at laboratory scale, obtained afterrecrystallizing from a mixture of ethanol and water (v/v=95:5) anddrying in vacuum oven.

FIG. 6 depicts an infrared (IR) spectrum of the crystalline form ofhalobetasol propionate at laboratory scale, obtained afterrecrystallizing from a mixture of ethanol and water (v/v=80:20) anddrying in vacuum oven.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

“Crystalline form” refers to a solid chemical compound that provides apattern of peaks when analyzed by x-ray powder diffraction; thisincludes polymorphs, solvates, hydrates, and desolvated solvates;“crystallization” refers to a process wherein a chemical compound thatis dissolved or suspended in a solvent system becomes a crystallineform; “solvent system” refers to a solvent or mixture of solvents; forpurposes of the present invention “crystallization” and“recrystallization” are used interchangeably; “isolating” refers toseparating a chemical compound (e.g., a crystalline form) from areaction mixture (e.g., a solvent system); according to the presentinvention, an isolated compound typically has a purity of at least about90% (w/w); “batch size” refers to the amount of a product compound(e.g., a crystalline form) produced during a chemical manufacturing step(e.g., a crystallization step); “rolling crystallization” refers to asolvent-mediated transformation of a solid compound into a crystallineform (See generally, Molecular Modeling Applications in Crystallization,Allan Myerson ed., Cambridge Univ. Press, 1999, 77-78); “ethanol” refersto a compound having the formula C₂H₅OH; “reflux temperature” refers tothe temperature at which a liquid boils; “purity” refers to thepercentage by weight (% w/w) of one component of a mixture; “purifying”refers to increasing the purity of a compound; “pharmaceutical grade”refers to a purity of at least about 99.0% (w/w); “precipitation” refersto a process wherein a solid forms in a solution; “slurrying” refers toagitating a suspension, e.g., by stirring; “suspension” refers to afluid that contains solid (i.e., undissolved) particles of a compound;“HPLC” refers to high performance liquid chromatography; “composition”refers to a solid chemical compound that has been synthesized by achemical reaction, isolated from the reaction mixture, and optionallypurified by (re)crystallization, together with any impurities that arepresent with the compound; “commercial scale composition” refers to acomposition that is produced as a single batch of at least about 100grams of the composition, and “laboratory scale” refers to one that hasless than about 100 grams of the composition.

Unless otherwise indicated, as expressed in the present specification aswell as in the set of claims as % weight refers to % wt/wt. % weightrefers to percentage of the weight of the referenced compound ascompared to the total weight of the composition. For purposes of thepresent invention, the term “about” refers to +/−10% of a specifiedvalue, as recognized by one skilled in the art.

The present invention provides a process for preparing a crystallineform of halobetasol propionate, comprising the step of crystallizinghalobetasol propionate from absolute ethanol (100%). The crystallineform of halobetasol propionate prepared by the process of the presentinvention is characterized by an x-ray powder diffraction pattern havingpeaks at 10.0, 11.6, 12.9, 13.4, 14.5, 16.4, 17.6, and 23.5±0.2 degrees2θ.

The present invention provides a process for preparing a crystallineform of halobetasol propionate, comprising the step of crystallizinghalobetasol propionate from a mixture of ethanol and water. Thecrystalline form of halobetasol propionate prepared by the process ofthe present invention is characterized by an x-ray powder diffractionpattern having peaks at 10.0, 11.6, 12.9, 13.4, 14.5, 16.4, 17.6, and23.5±0.2 degrees 2 θ.

Suitable processes for preparing halobetasol propionate are known in theart. For example, halobetasol propionate may be prepared by thefollowing three steps: (a) reacting diflorasone with an alkylorthopropionate reagent; (b) reacting the resulting diflorasone17-propionate with methanesulfonyl chloride; and (c) reacting theresulting diflorasone 17-propionate-21-mesylate with lithium chloride toform halobetasol propionate. This three-step process is described indetail in our copending application, U.S. Patent Application No.2003/0162959 A1 (the '959 application). An alternative method forpreparing halobetasol propionate is disclosed in U.S. Pat. No. 4,619,921(the '921 patent). The '959 application and '921 patent are incorporatedherein by reference in their entireties.

The diflorasone used in step (a) of the above-mentioned halobetasolpropionate synthesis process may be prepared by known methods (See,e.g., U.S. Pat. No. 3,557,158 (Example 24A), incorporated herein byreference in its entirety). For example, diflorasone may be prepared byhydrolysis of diflorasone diacetate using a process analogous to theprocess disclosed in Example IV of the '959 application. Diflorasonediacetate is commercially available (Sigma-Aldrich, St. Louis, Mo.), ormay be prepared by known methods.

The crystallizing step may be performed using any suitable method.Suitable methods for performing the crystallizing step include, but arenot limited to, solution crystallization and rolling crystallization.Preferably, the crystallizing step is performed by solutioncrystallization. Preferably, solution crystallization comprises thesteps of:

-   -   (a) preparing a solution of halobetasol propionate in absolute        ethanol; and    -   (b) inducing precipitation of a crystalline form of halobetasol        propionate.

Preferably, solution crystallization comprises the steps of:

-   -   (a) preparing a solution of halobetasol propionate in a mixture        of ethanol and water; and    -   (b) inducing precipitation of a crystalline form of halobetasol        propionate.

Preferably, rolling crystallization comprises the steps of:

-   -   (a) preparing a suspension of halobetasol propionate in a        mixture of ethanol and water, and    -   (b) slurrying the suspension to form a crystalline form of        halobetasol propionate.

The step (a) solution or step (a) suspension is prepared fromhalobetasol propionate. The halobetasol propionate may be crystalline,amorphous, semisolid, syrup, a mixture thereof, or the like. Crystallinehalobetasol propionate may include polymorphs, solvates, clathrates, andthe like, and mixtures thereof. Exemplary crystalline forms ofhalobetasol propionate include, but are not limited to, halobetasolpropionate Forms I, II, III, IV, V, and VI (See the '191 and '192applications).

Preferably, the step (a) solution or step (a) suspension is preparedfrom crude halobetasol propionate. “Crude halobetasol propionate” refersto halobetasol propionate that is synthesized by a chemical reaction andisolated from the reaction mixture, but not further purified. Processesfor preparing crude halobetasol propionate include, but are not limitedto, the processes set forth in U.S. Pat. No. 4,619,921 (Example 5) andU.S. Patent Application No. 2003/0162959 A1 (Example VIII).

With respect to the solution crystallization process, the step (a)solution may be prepared using any suitable method. Suitable methods forpreparing the step (a) solution include, but are not limited to, addinghalobetasol propionate to ethanol, and adding halobetasol propionate toa mixture of ethanol and water.

Preferably, the step (a) solution is prepared by heating a mixture ofhalobetasol propionate, ethanol, and water to an elevated temperature.More preferably, the step (a) solution is prepared by heating a mixtureof halobetasol propionate, ethanol, and water to a temperature of about60° C. to about 80° C. More preferably, the step (a) solution isprepared by heating a mixture of halobetasol propionate, ethanol, andwater to about the reflux temperature of the solution.

Optionally, the step (a) solution may be filtered prior to step (b).Preferably, the step (a) solution is hot filtered at an elevatedtemperature prior to step (b). More preferably, the step (a) solution ishot filtered at a temperature of about 60° C. to about 80° C. prior tostep (b). More preferably, the step (a) solution is hot filtered at atemperature of about 70° C. prior to step (b).

With respect to the optional filtering step, the step (a) solution maybe further purified by treatment with activated charcoal prior tofiltering. Activated charcoal is commercially available from NORITNederland B.V. (the Netherlands).

The optional filtering step may be performed using a filter aid.Suitable filter aids include, but are not limited to, diatomaceous earth(e.g., the active ingredient in CELITE®, manufactured and sold by WorldMinerals, Inc. (Santa Barbara, Calif.)).

With respect to step (b) of the solution crystallization process, thestep (b) precipitation may be induced using any suitable method.Suitable methods for inducing precipitation include, but are not limitedto, adding water to the step (a) solution, and cooling the step (a)solution.

Preferably, the step (b) precipitation is induced by slowly adding waterto the step (a) solution. More preferably, the step (b) precipitation isinduced by adding water to the step (a) solution over the course ofabout 30 minutes to about 90 minutes. More preferably, the step (b)precipitation is induced by adding water to the step (a) solution overthe course of about one (1) hour.

Preferably, the step (b) precipitation is induced by adding water to thestep (a) solution at an elevated temperature. More preferably, the step(b) precipitation is induced by adding water to the step (a) solution ata temperature of about 60° C. to about 80° C. More preferably, the step(b) precipitation is induced by adding water to the step (a) solution ata temperature of about 70° C.

Preferably, the step (b) precipitation is induced by cooling the step(a) solution. Preferably, the step (b) precipitation is induced bycooling the step (a) solution to a temperature of about 0° C. to about25° C. More preferably, the step (b) precipitation is induced by coolingthe step (a) solution to a temperature of about 18° C. to about 25° C.

Any suitable cooling rate may be used in the step (b) precipitation. Forexample, the step (b) precipitation may be induced by cooling the step(a) solution over the course of about five (5) minutes to about one (1)hour.

With respect to the rolling crystallization process, the step (a)suspension of halobetasol propionate may be prepared using any suitablemethod. Suitable methods for preparing the step (a) suspension include,but are not limited to, adding halobetasol propionate to a mixture ofethanol and water, optionally with cooling.

With respect to step (b) of the rolling crystallization process, theslurrying step (b) may be performed using any suitable method. Suitablemethods for performing the slurrying step (b) include, but are notlimited to, stirring the step (a) suspension.

The slurrying step (b) may be performed at any suitable temperature.Preferably, the slurrying step (b) is performed at about ambienttemperature or below. Preferably, the slurrying step (b) is performed ata temperature of about 0° C. to about 25° C. More preferably, theslurrying step (b) is performed at a temperature of about 18° C. toabout 25° C.

With respect to the crystallizing step of the present invention (e.g.,performed using solution crystallization or rolling crystallization),the crystallizing step may be performed using halobetasol propionate,ethanol, and water in any suitable proportions. Preferably, thecrystallizing step is performed at an ethanol to halobetasol propionateratio of about 3:1 to about 50:1 (w/w). More preferably, thecrystallizing step is performed at an ethanol to halobetasol propionateratio of about 5:1 to about 25:1 (w/w). More preferably, thecrystallizing step is performed at an ethanol to halobetasol propionateratio of about 10:1 (w/w).

Preferably, the crystallizing step is performed at an ethanol to waterratio of about 50:50 (v/v) to about 100:0 (v/v). More preferably, thecrystallizing step is performed at an ethanol to water ratio of about50:50 (v/v) to about 67:33 (v/v). More preferably, the crystallizingstep is performed at an ethanol to water ratio of about 50:50 (v/v).

Preferably, the process of the present invention further comprises thestep of isolating the crystalline form of halobetasol propionate fromthe mixture of ethanol and water after the crystallizing step. Suitableisolation methods include, but are not limited to, filtration,centrifugation, and decantation. Preferably, the isolating step isperformed by filtration.

Preferably, the isolated crystalline form of halobetasol propionate isdried. Preferably, the isolated crystalline form of halobetasolpropionate is dried at an elevated temperature. More preferably, theisolated crystalline form of halobetasol propionate is dried at atemperature of about 60° C. to about 80° C. More preferably, theisolated crystalline form of halobetasol propionate is dried at atemperature of about 65° C. to about 75° C.

Preferably, the isolated crystalline form of halobetasol propionate isdried at a reduced pressure. More preferably, the isolated crystallineform of halobetasol propionate is dried at a pressure of about 200 mbaror less. More preferably, the isolated crystalline form of halobetasolpropionate is dried at a pressure of about 100 mbar or less.

Repeated crystallization may increase the purity of the presentcrystalline form of halobetasol propionate. Preferably, thecrystallizing step is repeated at least once. In a preferred embodiment,the process for preparing the present crystalline form of halobetasolpropionate comprises the steps of:

-   -   (a) crystallizing halobetasol propionate from a first ethanol;    -   (b) isolating the crystallized halobetasol propionate from the        first ethanol;    -   (c) crystallizing the isolated halobetasol propionate from a        second ethanol; and    -   (d) isolating the crystallized halobetasol propionate from the        second ethanol.

In another preferred embodiment, the process for preparing the presentcrystalline form of halobetasol propionate comprises the steps of:

-   -   (a) crystallizing halobetasol propionate from a first mixture of        ethanol and water;    -   (b) isolating the crystallized halobetasol propionate from the        first mixture of ethanol and water;    -   (c) crystallizing the isolated halobetasol propionate from a        second mixture of ethanol and water; and    -   (d) isolating the crystallized halobetasol propionate from the        second mixture of ethanol and water.

Preferably, the ratio of ethanol to water in the first mixture is about50:50 (v/v). Preferably, the ratio of ethanol to water in the secondmixture is about 67:33 (v/v).

The present crystalline form of halobetasol propionate is characterizedby an x-ray powder diffraction pattern having peaks at 10.0, 11.6, 12.9,13.4, 14.5, 16.4, 17.6, and 23.5±0.2 degrees 2θ. The present crystallineform of halobetasol propionate is further characterized by an infraredspectrum having absorption peaks at 1741, 1709, 1665, 1627, and 1611±4cm⁻¹. The present crystalline form of halobetasol propionate is furthercharacterized by a melting point of about 220° C. to about 221° C.

Preliminary studies from our laboratory indicate that the presentcrystalline form of halobetasol propionate matches the crystalline formof halobetasol propionate present in ULTRAVATE® cream. An advantage ofthe present crystallization process is that it provides the commercialcrystalline form of halobetasol propionate.

A further advantage of the present invention is that the crystallizingstep is performed using ethanol or a mixture of ethanol and water, whichare non-toxic.

In a preferred embodiment, the process of the present invention isperformed at a commercial scale. Preferably, the present crystallineform of halobetasol propionate is produced as a single batch of at leastabout 100 grams. More preferably, the present crystalline form ofhalobetasol propionate is produced as a single batch of at least about500 grams. More preferably, the present crystalline form of halobetasolpropionate is produced as a single batch of at least about one (1)kilogram.

A further advantage of the present invention is that the presentcrystalline form of halobetasol propionate is produced in high yield.Preferably, the present crystalline form of halobetasol propionate isproduced in a yield of at least about 80% (w/w). More preferably, thepresent crystalline form of halobetasol propionate is produced in ayield of at least about 90% (w/w). More preferably, the presentcrystalline form of halobetasol propionate is produced in a yield of atleast about 95% (w/w).

In a preferred embodiment, the present crystallization process issuitable for the production of pharmaceutical grade halobetasolpropionate from crude halobetasol propionate. Preferably, the presentcrystalline form of halobetasol propionate has a purity of at leastabout 99.0% (w/w). More preferably, the present crystalline form ofhalobetasol propionate has a purity of at least about 99.5% (w/w). Morepreferably, the present crystalline form of halobetasol propionate has apurity of at least about 99.6% (w/w). More preferably, the presentcrystalline form of halobetasol propionate has a purity of at leastabout 99.7% (w/w). More preferably, the present crystalline form ofhalobetasol propionate has a purity of at least about 99.8% (w/w). Thepurity of the present crystalline form of halobetasol propionate may bedetermined as set forth below (See Methodology and Protocols).

Preferably, the present crystalline form of halobetasol propionatecontains about 0.1% (w/w) or less of each individual impurity. Examplesof possible impurities include, but are not limited to, diflorasone,diflorasone 17-propionate, halobetasol, diflorasone 21-propionate,diflorasone 17-propionate 21-mesylate, and6α,9α-difluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17(R)-spiro-2′-[4′-chloro-5′-ethylfuran-3-(2′H)-one].

Preferably, the present crystalline form of halobetasol propionatecontains about 0.1% (w/w) or less of diflorasone. More preferably, thepresent crystalline form of halobetasol propionate contains about 0.05%(w/w) or less of diflorasone. More preferably, the present crystallineform of halobetasol propionate contains about 0.02% (w/w) or less ofdiflorasone.

Preferably, the present crystalline form of halobetasol propionatecontains about 0.1% (w/w) or less of diflorasone 17-propionate.

Preferably, the present crystalline form of halobetasol propionatecontains about 0.1% (w/w) or less of halobetasol. More preferably, thepresent crystalline form of halobetasol propionate contains about 0.05%(w/w) or less of halobetasol. More preferably, the present crystallineform of halobetasol propionate contains about 0.02% (w/w) or less ofhalobetasol.

Preferably, the present crystalline form of halobetasol propionatecontains about 0.1% (w/w) or less of diflorasone 21-propionate. Morepreferably, the present crystalline form of halobetasol propionatecontains about 0.05% (w/w) or less of diflorasone 21-propionate. Morepreferably, the present crystalline form of halobetasol propionatecontains about 0.03% (w/w) or less of diflorasone 21-propionate.

Preferably, the present crystalline form of halobetasol propionatecontains about 0.1% (w/w) or less of diflorasone 17-propionate21-mesylate. More preferably, the present crystalline form ofhalobetasol propionate contains about 0.05% (w/w) or less of diflorasone17-propionate 21-mesylate. More preferably, the present crystalline formof halobetasol propionate contains about 0.03% (w/w) or less ofdiflorasone 17-propionate 21-mesylate.

Preferably, the present crystalline form of halobetasol propionatecontains about 0.1% (w/w) or less of6α,9α-difluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17(R)-spiro-2′-[4′-chloro-5′-ethylfuran-3-(2′H)-one].More preferably, the present crystalline form of halobetasol propionatecontains about 0.05% (w/w) or less of6α,9α-difluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17(R)-spiro-2′-[4′-chloro-5′-ethylfuran-3-(2′H)-one].

In a preferred embodiment, the present invention provides a commercialscale composition of a crystalline form of halobetasol propionateprepared by the process of the present invention.

In a preferred embodiment, the present invention provides a commercialscale composition of a crystalline form of halobetasol propionatecharacterized by an x-ray powder diffraction pattern having peaks at10.0, 11.6, 12.9, 13.4, 14.5, 16.4, 17.6, and 23.5±0.2 degrees 2θ,wherein the composition contains about 0.1% or less of each ofdiflorasone, diflorasone 17-propionate, halobetasol, diflorasone21-propionate, diflorasone 17-propionate 21-mesylate, and6α,9α-difluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17(R)-spiro-2′-[4′-chloro-5′-ethylfuran-3-(2′H)-one].Preferably, the commercial scale composition contains about 0.1% (w/w)or less of each impurity present in the composition.

Preferably, the commercial scale composition contains about 0.05% (w/w)or less of at least one of diflorasone, halobetasol, diflorasone21-propionate, diflorasone 17-propionate 21-mesylate, and6α,9α-difluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17(R)-spiro-2′-[4′-chloro-5′-ethylfuran-3-(2′H)-one].More preferably, the commercial scale composition contains about 0.05%(w/w) or less of each of diflorasone, halobetasol, diflorasone21-propionate, diflorasone 17-propionate 21-mesylate, and6α,9α-difluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17(R)-spiro-2′-[4′-chloro-5′-ethylfuran-3-(2′H)-one].

Preferably, the commercial scale composition contains about 0.03% (w/w)or less of at least one of diflorasone, halobetasol, diflorasone21-propionate, or diflorasone 17-propionate 21-mesylate. Morepreferably, the commercial scale composition contains about 0.03% (w/w)or less of each of diflorasone, halobetasol, diflorasone 21-propionate,and diflorasone 17-propionate 21-mesylate.

Preferably, the commercial scale composition contains about 0.02% (w/w)or less of at least one of diflorasone or halobetasol. More preferably,the commercial scale composition contains about 0.02% (w/w) or less ofeach of diflorasone and halobetasol.

Preferably, the commercial scale composition has a purity of at leastabout 99.5% (w/w). More preferably, the commercial scale composition hasa purity of at least about 99.6% (w/w). More preferably, the commercialscale composition has a purity of at least about 99.7% (w/w). Morepreferably, the commercial scale composition has a purity of at leastabout 99.8% (w/w).

As stated above, “composition” refers to a solid chemical compound thathas been synthesized by a chemical reaction, isolated from the reactionmixture, and optionally purified by (re)crystallization, together withany impurities that are present with the compound. Impurities areintended to include, but are not limited to, undesired side-productsformed during chemical synthesis. Examples of impurities that may bepresent in the composition include, but are not limited to, diflorasone,diflorasone 17-propionate, halobetasol, diflorasone 21-propionate,diflorasone 17-propionate 21-mesylate, and6α,9α-difluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17(R)-spiro-2′-[4′-chloro-5′-ethylfuran-3-(2′H)-one].

As stated above, “commercial scale composition” refers to a compositionthat is produced as a single batch of at least about 100 grams of thecomposition. Preferably, the composition is produced as a single batchof at least about 500 grams. More preferably, the composition isproduced as a single batch of at least about one (1) kilogram.

According to the invention, commercial scale compositions include, butare not limited to, commercial scale compositions that have not beensubjected to HPLC (high pressure liquid chromatography) purification,commercial scale compositions that have not been subjected torecrystallization, and commercial scale compositions that have not beensubjected to any purification procedure.

In a preferred embodiment, the present invention provides apharmaceutical formulation comprising the present crystalline form ofhalobetasol propionate. Further, there is provided a process forpreparing such a pharmaceutical formulation, comprising the step ofmixing the present crystalline form of halobetasol propionate with atleast one pharmaceutically acceptable excipient.

The present crystalline form of halobetasol propionate may, for example,conveniently be formulated for topical, oral, buccal, sublingual,parenteral, local or rectal administration. Topical pharmaceuticalformulations are preferred, such as creams, ointments, gels, pastes,foams, tinctures, solutions, and the like, which contain from about0.005% (w/w) to about 0.1% (w/w) of the present crystalline form ofhalobetasol propionate.

Ointments, creams and gels, may, for example, be formulated with anaqueous or oily base with the addition of a suitable thickening agent,gelling agent, and/or solvent. Such bases may thus, for example, includewater and/or an oil such as liquid paraffin or a vegetable oil such asarachis oil or castor oil, or a solvent such as polyethylene glycol.Thickening agents and gelling agents that may be used according to thenature of the base include soft paraffin, aluminium stearate,cetostearyl alcohol, polyethylene glycols, woolfat, beeswax,carboxypolymethylene and cellulose derivatives, and/or glycerylmonostearate and/or non-ionic emulsifying agents.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilizing agents,dispersing agents, suspending agents or thickening agents. Powders forexternal application may be formed with the aid of any suitable powderbase, for example, talc, lactose or starch. Drops may be formulated withan aqueous or non-aqueous base also comprising one or more dispersingagents, solubilizing agents, suspending agents or preservatives.

If appropriate, the formulations of the invention may be buffered by theaddition of suitable buffering agents.

Topical preparations may be administered by one or more applications perday to the affected area; over skin areas occlusive dressings mayadvantageously be used. Continuous or prolonged delivery may be achievedby an adhesive reservoir system.

For internal administration the compounds according to the inventionmay, for example, be formulated in conventional manner for oral,parenteral or rectal administration. Formulations for oraladministration include syrups, elixirs, powders, granules, tablets andcapsules which typically contain conventional excipients such as bindingagents, fillers, lubricants, disintegrants, wetting agents, suspendingagents, emulsifying agents, preservatives, buffer salts, flavoring,coloring and/or sweetening agents as appropriate.

Preferred forms of preparation for internal administration are dosageunit forms i.e. tablets and capsules. In general terms, preparations forinternal administration may contain from 0.01 to 10% (w/w) of thepresent crystalline form of halobetasol propionate dependent upon thetype of preparation involved. The daily dose may vary from 0.1 mg to 60mg, e.g. 5-30 mg, dependent on the condition being treated, and theduration of treatment desired.

Slow release or enteric coated formulations may be advantageous,particularly for the treatment of inflammatory bowel disorders.

Methodology and Protocols

X-Ray Powder Diffraction

X-ray powder diffraction (XRPD) patterns were obtained using a RigakuX-ray diffractometer Ultima 2200 with a Cu K_(α) (Ni) radiation source.The samples were run over the range from 5° to 40° with a step size of0.02° at a rate of 2 steps/second. The present crystalline form ofhalobetasol propionate is characterized by XRPD peaks at 10.0, 11.6,12.9, 13.4, 14.5, 16.4, 17.6, and 23.5±0.2 degrees 2θ. FIG. 1 depicts atypical x-ray powder diffraction pattern of the present crystalline formof halobetasol propionate.

Infrared Spectroscopy

Infrared (IR) spectra were obtained using a Nicolet Impact 410 FT-IRinstrument using potassium bromide pellets. The present crystalline formof halobetasol propionate is characterized by IR absorption peaks at1741, 1709, 1665, 1627, and 1611±4 cm⁻¹. Proposed peak assignments areprovided in the following table:

Wavenumber, cm⁻¹ Assignment 1741 C═O 1709 C═O 1665 C═O 1627 C═O 1611 C═C

FIG. 2 depicts a typical IR spectrum of the present crystalline form ofhalobetasol propionate.

Melting Point

Melting points were determined by a procedure analogous to the Procedurefor Class I, Apparatus I described in section <741> of the United StatesPharmacopeia. The melting point of the present crystalline form ofhalobetasol propionate is about 220° C. to about 221° C.

Purity

Purity was determined using a high performance liquid chromatography(HPLC) instrument with a variable wavelength detector.

(a) Chromatographic Conditions

Column Nova-Pak C18, 4 μm, 3.9*300 mm or equivalent Flow Rate 1.0 mL/minColumn temperature ambient Detection UV at 239 nm Injection volume 20 μLRun time 15 min for Standard solutions and Known Impurities solution 30min for Sample solution and Diluent Mobile phase 45:55 v/v Mixture ofWater and Acetonitrile Diluent Mobile phase

(b) Known Impurities Solution

The following known impurities were used: diflorasone(6α,9α-difluoro-11β,17,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione),diflorasone 17-propionate(6α,9α-difluoro-11β,17,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione,17-propionate), diflorasone 21-propionate(6α,9α-difluoro-11β,17,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione,21-propionate), diflorasone 17-propionate 21-mesylate(6α,9α-difluoro-11β,17,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione,17-propionate 21-mesylate), halobetsol((6α,11β,16β)-21-chloro-6,9-difluoro-11,17-dihydroxy-16-methylpregna-1,4-diene-3,20-dione),and “Impurity A”(6α,9α-difluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17(R)-spiro-2′-[4′-chloro-5′-ethylfuran-3-(2′H)-one]).

Each known impurity was added to a separate 10-mL volumetric flask, andeach flask was filled to volume with diluent. The solutions weresonicated to ensure complete dissolution. 5-mL aliquots of each solutionwere combined in a single 50-mL volumetric flask, and the flask wasfilled to volume with diluent. A 2-mL aliquot of the resulting solutionwas added to a 100-mL volumetric flask, together with 20 mg ofhalobetasol 17-propionate, and the flask was filled to volume withdiluent. The solution was sonicated to ensure complete dissolution.

(c) Crystalline Halobetasol Propionate Sample Solution

Approximately 20 mg of the crystalline halobetasol propionate sample tobe assayed, accurately weighed, was transferred into a 100-mL volumetricflask, and the flask was filled to volume with diluent. The solution wassonicated to ensure complete dissolution. The sample solution was stableat room temperature for 2 days protected from sunlight.

(d) Crystalline Halobetasol Propionate Standard Solution

Approximately 20 mg of a crystalline halobetasol propionate standard,accurately weighed, was transferred into a 100-mL volumetric flask, andthe flask was filled to volume with diluent. The solution was sonicatedto ensure complete dissolution. The standard solution was stable at roomtemperature for 2 days protected from sunlight.

(e) Standard Solution for Determination of Known Impurities

A 5-mL aliquot of the crystalline halobetasol propionate standardsolution was added to 100-mL volumetric flask, and the flask was filledto volume with diluent. A 2-mL aliquot of the resulting solution wasthen added to a 20-mL volumetric flask, and the flask was filled tovolume with diluent.

(f) HPLC Protocol

The known impurities solution, six replicate injections of the standardsolution for determination of known impurities, and five replicateinjections of the crystalline halobetasol propionate standard solutionwere made.

Resolution factors were calculated according to the United StatesPharmacopeia (USP) <621>. The resolution factor between diflorasone anddiflorasone 17-propionate, between diflorasone 17-propionate andhalobetasol, between diflorasone 21-propionate and diflorasone17-propionate 21-mesylate, between diflorasone 17-propionate 21-mesylateand halobetasol 17-propionate, and between halobetasol 17-propionate andimpurity A was not less than 2.0. The resolution factor betweenhalobetasol and diflorasone 21-propionate was not less than 1.3.

The relative standard deviation of five replicate injections of thecrystalline halobetasol propionate standard solution was not more than2.0%. The relative standard deviation of six replicate injections of thestandard solution for determination of known impurities was not morethan 10.0%. If necessary, the mobile phase composition and/or flow ratewere adjusted to meet the chromatographic parameters.

Typical chromatographic parameters are listed in the following table:

Relative Limit of Limit of Relative Retention Retention DetectionQuantitation Response Compound Time Time (LOD) (LOQ) Factor ResolutionDiflorasone 2.8 0.29 0.02% 0.03% 1.1 — Diflorasone 4.3 0.45 0.02% 0.03%1.0 9.5 17-propionate Halobetasol 4.8 0.51 0.02% 0.03% 1.0 2.7Diflorasone 5.1 0.54 0.02% 0.03% 1.0 1.5 21-propionate Diflorasone 7.40.78 0.02% 0.03% 0.8 10.3 17-propionate 21-mesylate Halobetasol 9.5 1.000.02% 0.03% 1.0 7.1 17-propionate Impurity A 10.5 1.11 0.02% 0.03% 1.03.2

The limit of detection is the minimum concentration at which the analytecan reliably be detected. The limit of quantitation is the minimumconcentration at which the analyte can reliably be quantified. Limits ofdetection and quantitation were determined by comparing measured signalsfrom samples with known low concentrations of analyte to measuredsignals from blank samples. The relative response factor is the ratio ofslopes provided by calibration curves for analyte and correspondinginternal standard (or surrogate and corresponding internal standard).The resolution is the separation of two peaks in terms of their averagepeak width at base (t_(R2)>t_(R1)):

${Resolution} = {\frac{\left( {t_{R\; 2} - t_{R\; 1}} \right)}{\left( {w_{b\; 1} + w_{b\; 2}} \right)/2} = \frac{2\left( {t_{R\; 2} - t_{R\; 1}} \right)}{\left( {w_{b\; 1} + w_{b\; 2}} \right)}}$

In the case of two adjacent peaks it may be assumed that w_(b1)=w_(b2),and thus, the width of the second peak may be substituted for theaverage value: Resolution=(t_(R2)−t_(R1))/w_(b2).

(g) Calculation of Purity

%  Purity = 100 − (%  known  impurities + %  unknown  impurities)${\%\mspace{14mu}{known}\mspace{14mu}{or}\mspace{14mu}{unknown}\mspace{14mu}{impurity}} = \frac{{Simp} \times 100}{{Simp} \times {RRF}}$Simp = Peak  area  of  impurity  obtained  from  crystalline  halobetasol  propionate  sample  solution  chromatogramSsum = Sum  of  the  areas  of  all  peaks  obtained  from  crystalline  halobetasol  propionate  sample  solution  chromatogramRRF = Relative  Response  Factor  (1.0  for  unknown  impurities)

EXAMPLES

The following Examples 1-4 were performed at a commercial scale.Analogous experiments (Examples 5-8) were performed at a laboratoryscale (i.e., batch sizes of less than 100 grams).

Example 1 Synthesis of Crude Halobetasol Propionate

Diflorasone 17-propionate 21-mesylate (1.65 kg) and lithium chloride(1.67 kg) were added to N,N-dimethylacetamide (16 L) in a 100-L reactionvessel. The resulting mixture was stirred under nitrogen at about 80° C.for 3 hours.

The mixture was then cooled to about 20° C. Water (45 L) was added overthe course of 50 minutes to the cooled mixture. The resulting mixturewas then stirred for about 1 hour at about 20° C. The resultingprecipitate was filtered and washed with water (20 L) to provide a wetcrude halobetasol propionate (2.84 kg; approximately 1.25 kg on a drybasis).

Example 2 Crystallization of Crude Halobetasol Propionate to Provide aCommercial Scale Composition of a Crystalline Form of HalobetasolPropionate

The wet crude halobetasol propionate prepared in Example 1 (2.84 kg) wasadded to ethanol (14 L) in a 100-L reaction vessel. The resultingmixture was heated at reflux (about 78° C.) for 30 minutes.

The mixture was then cooled to about 70° C. A suspension of activatedcarbon (0.14-kg) in ethanol (1 L) and a suspension of CELITE 545®(manufactured by Eagle-Picher Minerals Europe (Germany), activeingredient=siliceous earth) (0.14 kg) in ethanol (1 L) were added to thecooled mixture. The resulting mixture was heated at reflux (about 78°C.) for 30 minutes, and then hot filtered.

Water (16 L) was added to the resulting filtrate over the course of 55minutes at about 70° C. The resulting mixture was stirred at thistemperature for 30 minutes. The mixture was cooled to about 25° C., andthen stirred for 1 hour at 19-25° C. The resulting precipitate wasfiltered and washed with a mixture (4 L) of ethanol and water(v/v=50:50), to provide a crystalline form of halobetasol propionate(1.49 kg).

Example 3 Recrystallization of Halobetasol Propionate to Provide aCommercial Scale Composition of a Crystalline Form of HalobetasolPropionate

The crystalline form of halobetasol propionate prepared in Example 2(1.49 kg) was added to ethanol (15 L) in a 150-L reaction vessel. Theresulting mixture was heated at reflux (about 78° C.) for 30 minutes,and then transferred to a 100-L reactor.

Water (7.5 L) was added to the mixture over the course of 30 minutes ata temperature of about 71-73° C. The resulting mixture was stirred at70-71° C. for 30 minutes. The mixture was cooled to 25° C., and thenstirred for 1 hour at 20-25° C. The resulting precipitate was filteredand washed with a mixture (3 L) of ethanol and water (v/v=67:33), toprovide a crystalline form of halobetasol propionate as wet crystals(1.33 kg).

The wet crystalline form of halobetasol propionate was dried for 12hours at 70° C. under vacuum (80 mbar) to provide a crystalline form ofhalobetasol propionate. Yield=1.00 kg.

Example 4 Purity Determination

The purity of the crystalline form of halobetasol propionate prepared inExample 3 was determined using HPLC as set forth above (See Methodologyand Protocols). The quantities of known and unknown impurities arelisted in the following table:

Compound Quantity Diflorasone <0.02% (LOD) Diflorasone 17-propionate0.1% Halobetasol <0.02% (LOD) Diflorasone 21-propionate 0.03%Diflorasone 17-propionate 0.03% 21-mesylate Impurity A 0.05% Eachindividual unknown <0.02% (LOD) Total 0.2%

Accordingly, the purity of the crystalline form of halobetasolpropionate prepared in Example 3 was 99.8%.

Example 5 Recrystallization Using 100% Ethanol (Laboratory Scale) toObtain Crystalline Form of Halobetasol Propionate

Halobetasol propionate (1 gram) was added to absolute ethanol (5 mL;anhydrous alcohol). The resulting mixture was stirred and heated atabout 80° C. until the halobetasol was dissolved. The solution wasallowed to cool to room temperature and filtered. The resultingprecipitate was filtered and washed twice with the absolute ethanolreaction liquid. The sample was dried in vacuum oven at 60° C.Characterization of the samples by IR absorption peaks showed peaks at1741, 1709, 1665, 1627, and 1611±4 cm⁻¹. FIG. 3 shows the infraredspectroscopy of the obtained crystalline.

In an analogous study, halobetasol propionate (1 gram) wasrecrystallized from absolute ethanol (5 mL) as described above in thisExample. Instead of drying in vacuum over at 60° C., product was driedovernight on open air for 24 hours. FIG. 4 depicts the IR spectrum ofthe obtained sample under this drying condition. Comparison of IRspectrum between these two different drying conditions (i.e., vacuumoven at 60° C. vs. dried overnight on open air for 24 hours) revealsthat the same crystalline form of halobestaol propionate was obtainedafter crystallization from absolute ethanol despite the difference inthe drying conditions.

Example 6 Recrystallization Using 95% Ethanol (Laboratory Scale) toObtain Crystalline Form of Halobetasol Propionate

Halobetasol propionate (1 gram) was added to 95% ethanol (5 mL; amixture of ethanol and water at v/v of 95:5). The resulting mixture wasstirred and heated at about 80° C. until the halobetasol was dissolved.The solution was allowed to cool to room temperature and filtered. Theresulting precipitate was filtered and washed twice with the 95% ethanolreaction liquid. The sample was dried in vacuum over at 60° C.Characterization of the samples by IR absorption peaks showed peaks at1741, 1709, 1665, 1627, and 1611±4 cm⁻¹. FIG. 5 shows the infraredspectroscopy of the obtained crystalline. These studies show that thesame crystalline form of halobetasol propionate (i.e., Form III) wasobtained after crystallization using a mixture of ethanol and watereither at a laboratory scale or a commercial scale.

In an analogous study, halobetasol propionate (1 gram) wasrecrystallized from 95% ethanol (5 mL) as described above in thisExample. Instead of drying in vacuum over at 60° C., product was driedovernight on open air for 24 hours and 48 hours. Identical IR spectrawere obtained (data not shown) under these drying conditions, indicatingthat the same crystalline form of halobestaol propionate was obtainedafter crystallization from 95% ethanol despite different dryingconditions and duration.

Example 7 Recrystallization Using 80% Ethanol (Laboratory Scale) toObtain Crystalline Form of Halobetasol Propionate

Halobetasol propionate (1 gram) was added to 80% ethanol (5 mL; amixture of ethanol and water at v/v of 80:20). The resulting mixture wasstirred and heated at about 80° C. until the halobetasol was dissolved.The solution was allowed to cool to room temperature and filtered. Theresulting precipitate was filtered and washed twice with the 80% ethanolreaction liquid. The sample was dried in vacuum oven at 60° C.Characterization of the samples by IR absorption peaks showed peaks at1741, 1709, 1665, 1627, and 1611±4 cm⁻¹. FIG. 6 shows the infraredspectroscopy of the obtained crystalline.

In an analogous study, halobetasol propionate (1 gram) wasrecrystallized from 80% ethanol (5 mL) as described above in thisExample. Instead of drying in vacuum over at 60° C., product was driedovernight on open air for 24 hours and 48 hours. Identical IR spectrawere obtained (data not shown) under these drying conditions, indicatingthat the same crystalline form of halobestaol propionate was obtainedafter crystallization from 80% ethanol despite different dryingconditions and duration.

The citation and discussion of references in this specification isprovided merely to clarify the description of the present invention andis not an admission that any such reference is “prior art” to theinvention described herein. Each reference cited in this specificationis incorporated herein by reference in its entirety.

What is claimed is:
 1. A process for preparing a crystalline form ofhalobetasol propionate, comprising the step of crystallizing a singlebatch of at least about 100 grams of halobetasol propionate by (a)heating to a reflux temperature, halobetasol propionate in absoluteethanol or a mixture of between about 80:20 and about 100:0ethanol:water; (b) cooling the solution to induce precipitation, whereinthe crystalline form of halobetasol propionate is characterized by anx-ray powder diffraction pattern having peaks at 10.0, 11.6, 12.9, 13.4,14.5, 16.4, 17.6, and 23.5±0.2 degrees 2-theta.
 2. The process of claim1, wherein the crystalline form of halobetasol propionate is furthercharacterized by an infrared spectrum having absorption peaks at 1741,1709, 1665, 1627, and 1611±0.4 cm⁻¹.
 3. The process of claim 1, whereinstep (b) is performed by adding water to the prepared solution.
 4. Theprocess of claim 1, wherein step (b) is performed by adding water to theprepared solution over the course of about 30 minutes to about 90minutes.
 5. The process of claim 1, further comprising the step ofisolating the crystallized halobetasol propionate after step (b).
 6. Theprocess of claim 1, wherein the crystallizing step is repeated at leastonce.
 7. The process of claim 1, wherein the crystalline form ofhalobetasol propionate contains about 0.1% w/w or less of eachindividual impurity.
 8. The process of claim 1, wherein the crystallineform of halobetasol propionate contains about 0.02% w/w or less ofdiflorasone.
 9. The process of claim 1, wherein the crystalline form ofhalobetasol propionate contains about 0.02% w/w or less of halobetasol.10. The process of claim 1, wherein the crystalline form of halobetasolpropionate contains about 0.03% w/w or less of diflorasone21-propionate.
 11. The process of claim 1, wherein the crystalline formof halobetasol propionate contains about 0.03% w/w or less ofdiflorasone 17-propionate 21-mesylate.
 12. The process of claim 1,wherein the crystalline form of halobetasol propionate contains about0.05% w/w or less of6-alpha,9-alpha-difluoro-10-hydroxy-16-beta-methyl-3-oxoandrosta-1,4-diene-17(R)-spiro-2′-[4′-chloro-5′-ethylfuran-3-(2′H)-one].13. The process of claim 1, wherein the crystalline form of halobetasolpropionate is prepared as a single batch of at least about 500 grams.14. The process of claim 1, wherein the crystalline form of halobetasolpropionate is prepared as a single batch of at least about one kilogram.15. A process for preparing a crystalline form of halobetasolpropionate, comprising the steps of: (a) crystallizing a single batch ofat least about 100 grams of halobetasol propionate from a first ethanolsolution by heating to a reflux temperature, halobetasol propionate inabsolute ethanol or a mixture of between about 80:20 and about 100:0ethanol:water; (b) cooling the solution to induce precipitation; (c)isolating the crystallized halobetasol propionate from the first ethanolsolution; (d) crystallizing the isolated halobetasol propionate from asecond ethanol solution by heating to a reflux temperature, halobetasolpropionate in absolute ethanol or a mixture of between about 80:20 andabout 100:0 ethanol:water; (e) cooling the solution to induceprecipitation; (f) isolating the crystallized halobetasol propionatefrom the second ethanol solution, wherein the crystalline form ofhalobetasol propionate is characterized by an x-ray powder diffractionpattern having peaks at 10.0, 11.6, 12.9, 13.4, 14.5, 16.4, 17.6, and23.5±0.2 degrees 2-theta.
 16. The process of claim 15, wherein the firstethanol solution comprises water.
 17. The process of claim 15, whereinthe second ethanol solution comprises water.
 18. The process of claim15, wherein the crystalline form of halobetasol propionate is preparedas a single batch of at least about 500 grams.
 19. The process of claim15, wherein the crystalline form of halobetasol propionate is preparedas a single batch of at least about one kilogram.